Structure of the human P2Y12 receptor in complex with an antithrombotic drug.
P2Y receptors (P2YRs), a family of purinergic G-protein-coupled receptors (GPCRs), are activated by extracellular nucleotides. There are a total of eight distinct functional P2YRs expressed in human, which are subdivided into P2Y1-like receptors and P2Y12-like receptors. Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo, which limits our understanding of this receptor family. P2Y12R regulates platelet activation and thrombus formation, and several antithrombotic drugs targeting P2Y12R--including the prodrugs clopidogrel (Plavix) and prasugrel (Effient) that are metabolized and bind covalently, and the nucleoside analogue ticagrelor (Brilinta) that acts directly on the receptor--have been approved for the prevention of stroke and myocardial infarction. However, limitations of these drugs (for example, a very long half-life of clopidogrel action and a characteristic adverse effect profile of ticagrelor) suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors. Here we report the 2.6 Å resolution crystal structure of human P2Y12R in complex with a non-nucleotide reversible antagonist, AZD1283. The structure reveals a distinct straight conformation of helix V, which sets P2Y12R apart from all other known class A GPCR structures. With AZD1283 bound, the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic. Along with the details of the AZD1283-binding site, analysis of the extracellular interface reveals an adjacent ligand-binding region and suggests that both pockets could be required for dinucleotide binding. The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates.


Using Long-Term Volunteer Records to Examine Dormouse (Muscardinusavellanarius) Nestbox Selection.
Within ecology, there are unanswered questions about species-habitat interactions, which could potentially be resolved by a pragmatic analysis of a long-term volunteer-collected dataset. Here, we analysed 18 years of volunteer-collected data from a UK dormouse nestbox monitoring programme to determine the influence of habitat variables on nestbox choice by common dormice (Muscardinusavellanarius). We measured a range of habitat variables in a coppiced woodland in Gloucestershire, UK, and analysed these in relation to dormouse nestbox occupancy records (by dormice, other small mammals, and birds) collected by volunteers. While some characteristics of the woodland had changed over 18 years, simple transformation of the data and interpretation of the results indicated that the dataset was informative. Using stepwise regressions, multiple environmental and ecological factors were found to determine nestbox selection. Distance from the edge of the wood was the most influential (this did not change over 18 years), with boxes in the woodland interior being selected preferentially. There was a significant negative relationship with the presence of ferns (indicative of damp shady conditions). The presence of oak (a long-lived species), and the clumped structural complexity of the canopy were also important factors in the final model. There was no evidence of competition between dormice and birds or other mammals. The results provide greater understanding of artificial dormouse nest-site requirements and indicate that, in terms of habitat selection, long-term volunteer-collected datasets contribute usefully to understanding the requirements of species with an important conservation status.


Hematological and serum biochemical values in pregnant and postpartum females of the squirrel monkey (Saimiri sciureus).
The hematological and serum biochemical values of a total of 18 pregnant female squirrel monkeys were determined during the pre- and postpartum period. Pregnancy was determined by abdominal palpation in adult females cohabiting with robust males. The mean body weight of the pregnant females gradually increased toward parturition and dramatically decreased at parturition due to delivery of the infant monkey. The red blood cell count, hematocrit and hemoglobin levels diminished toward parturition and then increased to their normal levels by week 6 after delivery. The Wintrobe constant, MCHC, did not fluctuate, but MCH and MCV values increased in late pregnancy and the early nursing periods. The mean white blood cell count varied between 65.8 and 87.3 (x 10(2)/mm3) during the experimental periods. The mean serum total cholesterol concentration and glutamic-oxaloacetic transaminase activity were lower in the pregnant group during the mid- and late gestation stage than in nonpregnant and nursing females. The mean serum total protein and albumin values were lower in pregnant females than in the controls. Alkaline phosphatase activity increased in late pregnancy and the nursing periods. Since the pregnant females examined gave birth to healthy newborn monkeys and nursed them normally, the hematological and serum biochemical measurements should represent the physiological values for squirrel monkeys during pregnancy and the postpartum period.


Behavioral momentum and relapse of ethanol seeking: nondrug reinforcement in a context increases relative reinstatement.
Drug-related stimuli seem to contribute to the persistence of drug seeking and relapse. Behavioral momentum theory is a framework for understanding how the discriminative-stimulus context in which operant behavior occurs governs the persistence of that behavior. The theory suggests that both resistance to change and relapse are governed by the Pavlovian stimulus-reinforcer relation between a stimulus context and all sources of reinforcement obtained in that context. This experiment examined the role of the Pavlovian stimulus-reinforcer relation in reinstatement of ethanol seeking of rats by including added response-independent nondrug reinforcement in the self-administration context. Although rates of ethanol-maintained responding were lower in a context with added nondrug reinforcement than a context with ethanol alone, relative resistance to extinction and relative reinstatement were greater in the context previously associated with the nondrug reinforcer. Thus, both relative resistance to extinction and relative relapse of ethanol seeking depended on the Pavlovian stimulus-reinforcer relation between a context and all sources of reinforcement in that context. These findings suggest that to understand how drug-related contexts contribute to relapse, it may be necessary to consider not only the history of drug reinforcement in a context, but also the wide variety of other reinforcers obtained in such contexts.


Effects of trehalose on VEGF-stimulated angiogenesis and myofibroblast proliferation: implications for glaucoma filtration surgery.
To investigate whether trehalose inhibits VEGF-stimulated or inflammatory angiogenesis and the proliferation of myofibroblasts. Normal human dermal fibroblasts and human umbilical vein endothelial cells (HUVECs)were cocultured in trehalose-containing medium (2.5/5.0/7.5/10.0%) with or without VEGF (10 ng/mL). After 11 days, the area, length, joint, and path of neovascularization were evaluated. The effect of topical trehalose on corneal neovascularization was examined in vivo by treating Balb/c mice with alkali burn-induced corneal neovascularization. After 14 days of trehalose treatment, corneal vessels were visualized in flatmounts. The expressions of VEGFR2, phospho-VEGFR2, and vimentin were observed. Then a separate coculture model of the myofibroblasts and HUVECs was used to observe the morphologic changes of the myofibroblasts by trehalose. Furthermore, myofibroblasts were cultured with trehalose to examine the cytokeratin and E-cadherin expressions. In the in vitro models, there was a significant trehalose dose-dependent inhibition of neovascularization. In the in vivo alkali burn models, corneal neovascularization was significantly inhibited by treatments using ≥ 2.5% trehalose eyedrops. The expressions of VEGFR2, phospho-VEGFR2, and vimentin were downregulated by trehalose. When trehalose was added to the medium, the myofibroblasts were transformed into epithelial cell-like cells. The transformed myofibroblasts expressed cytokeratin but not E-cadherin. Trehalose prevents angiogenesis by partially downregulating VEGFR2 expression. In addition, trehalose inhibits the proliferation of myofibroblasts partially by inducing mesenchymal-epithelial transition. These findings suggest that trehalose has potential for use as a new agent that can control angiogenesis and fibrosis and potential for use in glaucoma surgery.


Immunosuppressive CD14+HLA-DR(low)/- monocytes in B-cell non-Hodgkin lymphoma.
Immunosuppression is a known risk factor for B-cell non-Hodgkin lymphoma (NHL), yet mechanisms of tumor-associated immunosuppression remain to be fully characterized. We examined the immunophenotype of 40 NHL patients and 27 age-matched healthy volunteers to better understand systemic immune suppression. NHL peripheral blood mononuclear cells had significantly decreased interferon-γ production and proliferation. This suppression was not the result of regulatory T cells, interleukin-6 or interleukin-10, as these factors were not different between NHL and healthy volunteers (controls). We were able to restore T-cell proliferation by removing NHL monocytes, suggesting that these monocytes are suppressive. This suppression was mediated in part through arginine metabolism as exogenous arginine supplementation partially overcame monocytes' suppression of T-cell proliferation in vitro and NHL patients had elevated arginase I in their plasma. NHL monocytes had impaired STAT1 phosphorylation and interferon-α production to CpG stimulation and a dendritic cell differentiation deficiency. Further studies demonstrated that monocytes from NHL patients had decreased HLA-DR and Tumor necrosis factor-α receptor II (CD120b) expression compared with controls (CD14(+)HLA-DR(low/-)CD120b(low)). Patients with increased ratios of CD14(+)HLA-DR(low/-) monocytes had more aggressive disease and suppressed immune functions. In summary, we report that CD14(+)HLA-DR(low/-) monocytes are a major and multifactorial contributor to systemic immunosuppression in NHL.


Epidemiology, Regional Characteristics, Knowledge, and Attitude Toward Female Genital Mutilation/Cutting in Southern Iran.
Female genital mutilation/cutting (FGM/C), also known as female circumcision, is an ancient traditional procedure that involves partial or total removal of the female external genitalia for nonmedical reasons. Although it is well described in African and some Arabic countries, data from Iran are scarce. To describe the epidemiology, regional characteristics, knowledge, and attitude toward FGM/C in Southern Iran. This cross-sectional study was conducted during a 36-month period from 2010 to 2013 in Hormozgan, a southern province of Iran near the Persian Gulf. We included 780 women in six major rural areas of the province who referred to healthcare centers for vaccination, midwifery, or family planning services. All participants underwent complete pelvic examination to determine the type of FGM. The questionnaire consisted of several sections such as demographic and baseline characteristics, and two self-report sections addressing the knowledge and attitude toward FGM/C and its complications. Baseline sociodemographic characteristics including age, educational level, marital status, religion, and nationality were the independent variables. Among the participants, 535 (68.5%) had undergone FGM/C. FGM/C was associated with higher age (P = 0.002), Afghan nationality (P = 0.003), Sunni Islam as religion (P = 0.019), illiteracy (P < 0.001), and family history of FGM/C in mother (P < 0.001), sister (P < 0.001), and grandmother (P < 0.001). Ancient traditions in the area (57.1%) were mentioned as the most important factor leading to FMG/C. Urinary tract infection was the most common reported complication (60.4%). FGM/C is a common practice in rural areas of Southern Iran. It is associated with increased age, illiteracy, Sunni Islam religion, Afghan nationality, and positive family history. Lack of knowledge toward FGM/C is the main cause of its high prevalence and continuation in the area.


Effects of moderate and vigorous physical activity on heart rate variability in a British study of civil servants.
Physical inactivity and low resting heart rate variability (HRV) are associated with increased coronary heart disease incidence. In the Whitehall II study of civil servants aged 45-68 years (London, United Kingdom, 1997-1999), the strength of the association of moderate and vigorous activity with higher HRV was examined. Five-minute recordings of heart rate and HRV measures were obtained from 3328 participants. Calculated were time domain (standard deviation of NN intervals) and high-frequency-power measures as indicators of cardiac parasympathetic activity and low-frequency power of parasympathetic-sympathetic balance. Leisure-time physical activity (metabolic equivalent-hours per week) was categorized as moderate (>or=3-<5) and vigorous (>or=5). Moderate and vigorous physical activity were associated with higher HRV and lower heart rate. For men, linear trends of higher low-frequency power with increasing quartile of vigorous activity (304.6 (low), 329.0, 342.4, 362.5 (high); p < 0.01) and lower heart rate with increasing quartile of moderate activity (69.6 (low), 69.2, 68.9, 67.8 (high); p < 0.05) were found. These associations remained significant after adjustment for smoking and high alcohol intake. For men whose body mass index was >25 kg/m(2), vigorous activity was associated with HRV levels similar to those for normal-weight men who engaged in no vigorous activity. Vigorous activity was associated with higher HRV, representing a possible mechanism by which physical activity reduces coronary heart disease risk.


The Rightful Demise of the Sh*t Sandwich: Providing Effective Feedback.
As a trainee cognitive therapist in the early 1990s, I was taught the Sh*t Sandwich by my supervisor. I continued to use this technique for many years without seeing the need to extend my repertoire of feedback strategies. This article describes a number of other feedback techniques, raising awareness of the processes underpinning feedback, and facilitating reflection on feedback methods. This review examines feedback and the methods of feedback used to improve clinical competence. Evidence informs us that the use of good feedback has a significant effect on learners' outcomes (Milne, 2009). However, despite recognition of its importance, many supervisors fail to give adequate feedback and utilize methods that are sub-optimal. One such problematic method is the notorious "Sh*t Sandwich" (SS), which attempts to hide criticism within a cushion of two positive statements. This paper looks at various models of giving negative and positive feedback, suggesting that our repertoire of feedback methods may require expanding. The review suggests that feedback is a complex process and methods that place an emphasis on the learner as an active participant in the learning process (i.e. interactive approaches) should be encouraged. The paper suggests that negative feedback should generally be avoided in favour of constructive support, accompanied by specific, descriptive, balanced feedback, with new learning being consolidated by role play. Generally, feedback should be given about the task rather than the person, but when it is personalized it should relate to effort rather than ability.


Impact of depression and recreational drug use on emergency department encounters and hospital admissions among people living with HIV in Ontario: A secondary analysis using the OHTN cohort study.
Nearly half of HIV-positive patients experience mental health and substance use problems, but many do not receive adequate or ongoing mental health or addiction care. This lack of ongoing care can result in the use of costly acute care services. Prospective evaluations of the relationship between psychiatric and substance use disorders and acute care services use are lacking, and this information is needed to understand unmet needs and improve access to appropriate services. We conducted a secondary data analysis from a multicenter, longitudinal, prospective cohort study (n = 3,482 adults) between October 1, 2007 and March 31, 2013. We used explanatory extended Cox proportional hazard regression models to examine the impact of current depression and recreational drug use on acute care services use, and to explore whether current depression and recreational drug use were associated with potentially avoidable acute care services use. Over our 5.5 year study period, HIV-positive participants with current depression-only (aHR [95% CI]:1.2[1.1-1.4]), recreational drug use-only (1.3[1.1-1.6]), or co-occurring depression and recreational drug use (1.4[1.2-1.7]) were associated with elevated hazard of emergency department (ED) encounters compared to participants without these conditions. Over half of ED encounters were potentially avoidable. Participants with current depression-only (1.3[1.1-1.5];1.3[1.03-1.6]), recreational drug use-only (1.3[1.04-1.6];1.5[1.1-1.9]), or co-occurring depression and recreational drug use (1.3[1.04-1.7];1.4[1.06-1.9]) were associated with elevated hazard of low-acuity or repeated ED encounters respectively. We found a significant increase in ED services use and potentially avoidable ED encounters (including low-acuity or repeated ED encounters), particularly among those with either current depression or recreational drug use. These findings emphasize the challenges in managing HIV and mental health/addiction co-morbidities in the current HIV care model. Future research should evaluate integrated and collaborative care programs for improving the coordination of care and effectively treat mental health and addiction problems among HIV-positive patients in Ontario.


Danger-Associated Peptides Interact with PIN-Dependent Local Auxin Distribution to Inhibit Root Growth in Arabidopsis.
Plant elicitor peptides (Peps) are damage/danger-associated molecular patterns that are perceived by the receptor-like kinases, PEPR1 and PEPR2, to enhance innate immunity and to inhibit root growth in Arabidopsis (Arabidopsis thaliana). Here, we show that Arabidopsis Pep1 inhibits root growth in a PEPR2-dependent manner, which is accompanied by swelling epidermal and cortex cells and root hair formation in the transition zone (TZ). These Pep1-induced changes were mimicked by exogenous auxin application and were suppressed in the auxin perception mutants transport inhibitor response1 (tir1) and tir1 afb1 afb2 Pep1-induced auxin accumulation in the TZ region preceded cell expansion in roots. Because local auxin distribution depends on PIN-type auxin transporters, we examined Pep1-PEPR-induced root growth inhibition in several pin mutants and found that pin2 was highly sensitive but pin3 was less sensitive to Pep1. The pin2 pin3 double mutant was as sensitive to Pep1 treatment as wild-type plants. Pep1 reduced the abundance of PIN2 in the plasma membrane through activating endocytosis while increasing PIN3 expression in the TZ, leading to changes in local auxin distribution and inhibiting root growth. These results suggest that Pep-PEPR signaling undergoes crosstalk with auxin accumulation to control cell expansion and differentiation in roots during immune responses.


Sex differences in binding of human growth hormone to isolated rat hepatocytes.
Since liver is a target for growth hormone action, binding of 125I-labeled human growth hormone to enzymatically isolated rat hepatocytes was studied. Specific binding was shown with hepatocytes from both male and female animals. There was a single class of receptors for human growth hormone on cells from males (affinity constant, Ka = 1.16 x 10(9) liters/mole; sites per cell, q = 6200). In males, bovine growth hormone was almost as potent as human growth hormone in displacing bound 125I-labeled human growth hormone, while ovine prolactin was about 1000 times less potent. Cells from female rats bound more 125I-labeled human growth hormone than cells from males. The cells from females contained at least two classes of receptors for human growth hormone. The receptor of highest affinity had the same affinity for human growth hormone as the single receptor found in males (Ka = 0.96 x 10(9) liters/mole). However, there were three to four times as many of these receptors per cell in females (q = 21,000). In females, bovine growth hormone and ovine prolactin were both about 20 times less potent than human growth hormone. Treatment of male rats with estrone produced cells that show the same binding characteristics as females. These results indicate that human growth hormone binds to a somatogenic receptor in hepatocytes from male rats. In females and estrogen-treated males, the receptors that bind human growth hormone recognize lactogenic as well as somatogenic properties. This suggests that the lactogenic and growth-promoting effects of human growth hormone in the rat are mediated by different receptors.


Magnetization reversal of ferromagnetic nanosprings affected by helical shape.
Helicity, a natural property of macro-, micro-, and nano-objects, potentially offers a new dimension to mechanical and electromagnetic applications for creating emerging nanodevices, such as nanorobots, nanomagnets, nanosensors, and high-density magnetic memory. Helical magnetic nanosprings are unique objects with remarkable magnetic properties, including the absence of stray fields in remanence owing to the chiral geometry, which makes them promising for data storage devices, nanoelectromechanical systems, and biomedical usage. Here, we investigated Co and CoFe nanospring arrays electrodeposited in highly ordered nanoporous templates. We report helical-shape-driven magnetization reversal of the nanosprings in comparison with the behavior of dipolarly coupled nanowires. We reveal two magnetization reversal modes depending on the orientation of the external magnetic field: coherent rotation of magnetization in the longitudinal geometry and three-dimensional vortex domain wall motion in the transverse geometry. The experimental findings are supported by analytical calculations and micromagnetic simulations that help to explain the field-dependent spin configurations observed by magnetic force microscopy.


Sex-related effects of reproduction on biomarkers of oxidative damage in free-living barn swallows (Hirundo rustica).
According to life-history theory, the allocation of limiting resources to one trait has negative consequences for other traits requiring the same resource, resulting in trade-offs among life-history traits, such as reproduction and survival. In vertebrates, oxidative stress is increasingly being considered among the physiological mechanisms forming the currency of life-history trade-offs. In this study of the barn swallow (Hirundo rustica), we focus on the oxidative costs of reproduction, especially egg laying, by investigating the effects of breeding stage (pre- vs. post-laying) and progression of the season on three biomarkers of oxidative damage (OD) to plasma proteins, namely the concentration of malondialdehyde (MDA)-protein adducts and of protein thiol groups (PSH), and the protein carbonyl (PCO) content. Moreover, we investigated whether males and females differed in plasma OD levels, because the inherent sex differences in reproductive roles and physiology may originate sex-specific patterns of OD during breeding. We found that MDA-protein adduct levels were higher in the pre-laying than in the post-laying phase, that males had lower levels of MDA-modified proteins than females, and that the decline of MDA-protein adduct concentration between the pre- and the post-laying phase was more marked for females than males. In addition, MDA-protein adduct levels declined with sampling date, but only during the pre-laying phase. On the other hand, plasma PCO levels increased from the pre- to the post-laying phase in both sexes, and females had higher levels of PCO than males. PSH concentration was unaffected by breeding stage, sex or sampling date. On the whole, our findings indicate that biomarkers of protein oxidation closely track the short-term variation in breeding stage of both male and female barn swallows. Moreover, the higher protein OD levels observed among females compared to males suggest that egg laying entails oxidative costs, which might negatively affect female residual reproductive value.


The subliminal perception of movement and the 'suppression' in binocular rivalry.
An analogy is drawn between the perceptual limitation that characterizes the dichotic listening paradigm and the 'suppression' that occurs in binocular rivalry when different stimuli are presented to the two eyes. An experiment is reported which focuses on the fate of the information residing in a suppressed eye (unattended channel) during binocular rivalry. It is demonstrated that the temporal course of rivalry is sensitive to the presence of a subliminal moving stimulus within the currently suppressed field. The effects are seen to confirm a literal interpretation of Levelt's (1966) thesis which relates changes in the 'stimulus strength' of a rivalling field to subsequent changes in the temporal course of the phenomenon. This interpretation is consistent with the hypothesis that, despite phenomenal suppression, a full analysis is undertaken on the currently non-dominant stimulus. The data are related to models of selective attention, and to the notion that there are parallel visual systems.


Predictors of recurrence in primary hyperparathyroidism: an analysis of 1386 cases.
The purpose of this study was to determine whether the operative approach independently influenced recurrence and to identify perioperative predictors of recurrence. Intraoperative parathyroid hormone (IoPTH) monitoring has enabled surgeons to perform minimally invasive parathyroidectomy (MIP). Yet, the long-term durability of this approach has recently been questioned. A retrospective review was performed, and cases of initial neck surgery for nonfamilial primary hyperparathyroidism were selected for analysis. Cases were classified as either open parathyroidectomy (OP) when both sides of the neck were explored or MIP when only one side was explored. Kaplan-Meier estimates were plotted for disease-free survival, and a Cox proportional hazards model was developed to evaluate factors associated with recurrence for both the entire cohort and the MIP subset. Further comparisons were made between those who recurred and those who did not recur. In the past 10-year period, 1368 parathyroid operations for primary hyperparathyroidism were performed at our institution. A total of 1006 were MIP whereas 380 were OP. There were no differences in recurrence between the MIP and OP groups (2.5% vs 2.1%; P = 0.68), and the operative approach (MIP vs OP) did not independently predict recurrent disease in our multivariate analysis. The percentage decrease in IoPTH was protective against recurrence for both the entire cohort (hazard ratio = 0.96; 95% confidence interval = 0.93-0.99; P = 0.03) and the MIP subset. A higher postoperative PTH also independently predicted disease recurrence. Operative approach does not independently predict recurrent hyperparathyroidism. The percentage decrease in IoPTH is one of many adjuncts the surgeon can use to determine which patients are best served by bilateral exploration whereas the postoperative PTH can guide follow-up after parathyroidectomy.


Wnt11 and Ret/Gdnf pathways cooperate in regulating ureteric branching during metanephric kidney development.
Reciprocal cell-cell interactions between the ureteric epithelium and the metanephric mesenchyme are needed to drive growth and differentiation of the embryonic kidney to completion. Branching morphogenesis of the Wolffian duct derived ureteric bud is integral in the generation of ureteric tips and the elaboration of the collecting duct system. Wnt11, a member of the Wnt superfamily of secreted glycoproteins, which have important regulatory functions during vertebrate embryonic development, is specifically expressed in the tips of the branching ureteric epithelium. In this work, we explore the role of Wnt11 in ureteric branching and use a targeted mutation of the Wnt11 locus as an entrance point into investigating the genetic control of collecting duct morphogenesis. Mutation of the Wnt11 gene results in ureteric branching morphogenesis defects and consequent kidney hypoplasia in newborn mice. Wnt11 functions, in part, by maintaining normal expression levels of the gene encoding glial cell-derived neurotrophic factor (Gdnf). Gdnf encodes a mesenchymally produced ligand for the Ret tyrosine kinase receptor that is crucial for normal ureteric branching. Conversely, Wnt11 expression is reduced in the absence of Ret/Gdnf signaling. Consistent with the idea that reciprocal interaction between Wnt11 and Ret/Gdnf regulates the branching process, Wnt11 and Ret mutations synergistically interact in ureteric branching morphogenesis. Based on these observations, we conclude that Wnt11 and Ret/Gdnf cooperate in a positive autoregulatory feedback loop to coordinate ureteric branching by maintaining an appropriate balance of Wnt11-expressing ureteric epithelium and Gdnf-expressing mesenchyme to ensure continued metanephric development.


A family of putative potassium channel genes in Drosophila.
Mutant flies in which the gene coding for the Shaker potassium channel is deleted still have potassium currents similar to those coded by the Shaker gene. This suggests the presence of a family of Shaker-like genes in Drosophila. By using a Shaker complementary DNA probe and low-stringency hybridization, three additional family members have now been isolated, Shab, Shaw, and Shal. The Shaker family genes are not clustered in the genome. The deduced proteins of Shab, Shaw, and Shal have high homology to the Shaker protein; the sequence identity of the integral membrane portions is greater than 50 percent. These genes are organized similarly to Shaker in that only a single homology domain containing six presumed membrane-spanning segments common to all voltage-gated ion channels is coded by each messenger RNA. Thus, potassium channel diversity could result from an extended gene family, as well as from alternate splicing of the Shaker primary transcript.


Anorexia nervosa symptoms are reduced by massage therapy.
Nineteen women (M age = 26) diagnosed with anorexia nervosa were given standard treatment alone or standard treatment plus massage therapy twice per week for five weeks. The massage group reported lower stress and anxiety levels and had lower cortisol (stress) hormone levels following massage. Over the five-week treatment period, they also reported decreases in body dissatisfaction on the Eating Disorder Inventory and showed increased dopamine and norepinephrine levels. These findings support a previous study on the benefits of massage therapy for eating disorders.


Socrates: identification of genomic rearrangements in tumour genomes by re-aligning soft clipped reads.
Methods for detecting somatic genome rearrangements in tumours using next-generation sequencing are vital in cancer genomics. Available algorithms use one or more sources of evidence, such as read depth, paired-end reads or split reads to predict structural variants. However, the problem remains challenging due to the significant computational burden and high false-positive or false-negative rates. In this article, we present Socrates (SOft Clip re-alignment To idEntify Structural variants), a highly efficient and effective method for detecting genomic rearrangements in tumours that uses only split-read data. Socrates has single-nucleotide resolution, identifies micro-homologies and untemplated sequence at break points, has high sensitivity and high specificity and takes advantage of parallelism for efficient use of resources. We demonstrate using simulated and real data that Socrates performs well compared with a number of existing structural variant detection tools. Socrates is released as open source and available from http://bioinf.wehi.edu.au/socrates CONTACT: email@example.com Supplementary information: Supplementary data are available at Bioinformatics online.


Evaluation of the Taking Texas Tobacco Free Workplace Program within behavioral health centers.
Despite the health benefits of tobacco control and cessation initiatives, tobacco users with behavioral health disorders (BHDs) have less access to evidence-based tobacco dependence treatment. Academic-community partnerships can help guide the translation of tobacco-related research findings and evidence-based guidelines into real-world applications. Through a comprehensive, evidence-based, multilevel, and multicomponent program, Taking Texas Tobacco Free (TTTF) facilitated the implementation of tobacco-free workplaces at 18 local mental health authorities in Texas, comprising over 250 individual community behavioral health centers. Compared with preprogram implementation, key accomplishments postimplementation include: (1) educated over 5,000 employees (nonclinical staff and providers) on the hazards of tobacco use and benefits of quitting, particularly among people with BHD; providers were additionally trained on the use of evidence based practices (EBPs; i.e. 5A's model, use of pharmacotherapy) to identify and treat tobacco use among people with BHD; (2) providers' significant increase in conducting tobacco-use assessments and using EBPs; (3) significant decrease in nonclinical staff tobacco use; (4) increase in quit attempts among consumers as evidenced by the demand for nicotine replacement therapy; and (5) reach to over 115,000 community members through outreach and education about the benefits of quitting tobacco use and maintaining a healthy lifestyle. TTTF demonstrated that the implementation of a comprehensive tobacco-free workplace program in behavioral health settings is feasible and beneficial, facilitating the capacity building of healthcare professionals and enhancing their resulting engagement in EBPs, and promoting healthier lifestyles among employees, consumers, and community members as a whole.


Selective testing for calreticulin gene mutations in patients with splanchnic vein thrombosis: A prospective cohort study.
Myeloproliferative neoplasms (MPN) are the leading cause of splanchnic vein thrombosis (SVT). Janus kinase 2 gene (JAK2)V617F mutations are found in 80 to 90% of patients with SVT and MPN. Mutations of the calreticulin (CALR) gene have also been reported. However, as their prevalence ranges from 0 to 2%, the utility of routine testing is questionable. This study aimed to identify a group of patients with SVT at high risk of harboring CALR mutations and thus requiring this genetic testing. CALR, JAK2V617F and thrombopoietin receptor gene (MPL) mutations were analysed in a test cohort that included 312 patients with SVT. Criteria to identify patients at high risk of CALR mutations in this test cohort was used and evaluated in a validation cohort that included 209 patients with SVT. In the test cohort, 59 patients had JAK2V617F, five had CALR and none had MPL mutations. Patients with CALR mutations had higher spleen height and platelet count than patients without these mutations. All patients with CALR mutations had a spleen height ⩾16cm and platelet count >200×109/L. These criteria had a positive predictive value of 56% (5/9) and a negative predictive value of 100% (0/233) for the identification of CALR mutations. In the validation cohort, these criteria had a positive predictive value of 33% (2/6) and a negative predictive value of 99% (1/96). CALR mutations should be tested in patients with SVT, a spleen height ⩾16cm, platelet count >200×109/L, and no JAK2V617F. This strategy avoids 96% of unnecessary CALR mutations testing. Lay summary: Mutations of the CALR gene are detected in 0 to 2% of patients with SVT, thus the utility of systematic CALR mutation testing to diagnose MPN is questionable. This study demonstrates that CALR mutations testing can be restricted to patients with SVT, a spleen height ⩾16cm, a platelet count >200×109/L, and no JAK2V617F. This strategy avoids 96% of unnecessary CALR mutations testing.


Facile catalyst separation without water: fluorous biphase hydroformylation of olefins.
A novel concept for performing stoichiometric and catalytic chemical transformations has been developed that is based on the limited miscibility of partially or fully fluorinated compounds with nonfluorinated compounds. A fluorous biphase system (FBS) consists of a fluorous phase containing a dissolved reagent or catalyst and another phase, which could be any common organic or nonorganic solvent with limited or no solubility in the fluorous phase. The fluorous phase is defined as the fluorocarbon (mostly perfluorinated alkanes, ethers, and tertiary amines)-rich phase of a biphase system. An FBS compatible reagent or catalyst contains enough fluorous moieties that it will be soluble only or preferentially in the fluorous phase. The most effective fluorous moieties are linear or branched perfluoroalkyl chains with high carbon number; they may also contain heteroatoms. The chemical transformation may occur either in the fluorous phase or at the interface of the two phases. The application of FBS has been demonstrated for the extraction of rhodium from toluene and for the hydroformylation of olefins. The ability to separate a catalyst or a reagent from the products completely at mild conditions could lead to industrial application of homogeneous catalysts or reagents and to the development of more environmentally benign processes.


Morphological and mechanical properties of the human triceps surae aponeuroses taken from elderly cadavers: Implications for muscle-tendon interactions.
The human triceps surae (two gastrocnemii and soleus) has aponeuroses in the proximal and distal aspects, the latter of which insert into the calcaneus by sharing the common Achilles tendon. These tendinous tissues are known to have elasticity and upon muscle contraction the aponeurosis is stretched both longitudinally (along the muscle's line of action) and transversely. Higher aponeurosis transverse deformability has been documented, but there is a paucity of information on the morphology and mechanical properties of human aponeurosis. This study aimed to identify morphological and mechanical characteristics of the human triceps surae aponeuroses. Twenty-five triceps surae muscle-tendon units were procured from 13 human donors (formalin fixed, 6 males, 7 females) aged 67-91 years. Specimens of aponeuroses were excised from the eight regions (posterior and anterior regions of the gastrocnemius medialis and lateralis, medial and lateral parts of soleus; proximal, middle, and distal sites each, 2-4 cm × 2-4 cm). Aponeurosis thickness was measured using a digital caliper. Uniaxial tensile tests were implemented to determine the mechanical properties of specimens loaded longitudinally (along the muscle's line of action) and transversely. The aponeurosis thickness showed significant differences between muscles and sites, while Young's modulus showed direction-dependent (longitudinal vs. transverse) differences within sites. Results show different morphology and mechanical properties of aponeuroses between synergist muscles. The reason for site-dependent differences in stiffness is due to a reduced aponeurosis thickness rather than a reduction in the material property. The anisotropic elastic feature (differences between longitudinal and transverse directions) of the aponeuroses was more pronounced than previous in vivo findings, suggesting inherent material design of the aponeurosis that matches three-dimensional contractile behavior of muscle fibers.


Psychiatric disorders and mortality among people in homeless shelters in Denmark: a nationwide register-based cohort study.
The increased mortality of homeless people compared with non-homeless people might be linked to psychiatric disorders. However, homeless people are, because of their insufficient accommodation, difficult to sample and monitor, which has limited previous studies. We aimed to assess registered psychiatric disorders, mortality, and predictors of mortality in the homeless shelter population in Denmark. We did a nationwide, prospective, register-based cohort study of homeless people aged 16 years and older who were registered in the Danish Homeless Register between Jan 1, 1999, and Dec 31, 2009. We calculated the proportion of registered psychiatric disorders, overall and cause-specific standardised mortality ratio (SMR), and life expectancy. Hazard ratios (HRs) were used to assess predictors of death. 32,711 homeless people (23,040 men and 9671 women) were included in the study population. 14,381 men (62·4%) and 5632 women (58·2%) had registered psychiatric disorders, and 11,286 men (49·0%) and 3564 women (36·9%) had a substance abuse diagnosis. During the study period, 3839 men (16·7%) and 951 women (9·8%) died. The overall SMR for men was 5·6 (95% CI 5·4-5·8) and for women was 6·7 (6·2-7·1), and external causes accounted for 1161 (27·9%) of 4161 deaths for which information on the cause was available. Remaining life expectancy at age 15-24 years was 21·6 years (95% CI 21·2-22·1) and 17·4 years (16·4-18·5) lower for homeless men and women, respectively, than the general population. Registered substance abuse disorder was associated with the highest mortality risk compared with no psychiatric contact registered (adjusted HR 1·4, 95% CI 1·3-1·5 for men; 1·7, 1·4-2·1 for women). Health problems are extensive in the homeless shelter population and there is an urgent need for more sustained efforts to reduce the high morbidity and mortality, especially from external causes. Register data is an important resource to supplement existing knowledge on homeless people with more valid and detailed information. The Danish Council for Independent Research.


Point of care information services: a platform for self-directed continuing medical education for front line decision makers.
The structure and aim of continuing medical education (CME) is shifting from the passive transmission of knowledge to a competency-based model focused on professional development. Self-directed learning is emerging as the foremost educational method for advancing competency-based CME. In a field marked by the constant expansion of knowledge, self-directed learning allows physicians to tailor their learning strategy to meet the information needs of practice. Point of care information services are innovative tools that provide health professionals with digested evidence at the front line to guide decision making. By mobilising self-directing learning to meet the information needs of clinicians at the bedside, point of care information services represent a promising platform for competency-based CME. Several points, however, must be considered to enhance the accessibility and development of these tools to improve competency-based CME and the quality of care.


An in silico model of cytotoxic T-lymphocyte activation in the lymph node following short peptide vaccination.
Tumour immunotherapy is dependent upon activation and expansion of tumour-targetting immune cells, known as cytotoxic T-lymphocytes (CTLs). Cancer vaccines developed in the past have had limited success and the mechanisms resulting in failure are not well characterized. To elucidate these mechanisms, we developed a human-parametrized, in silico, agent-based model of vaccination-driven CTL activation within a clinical short-peptide vaccination context. The simulations predict a sharp transition in the probability of CTL activation, which occurs with variation in the separation rate (or off-rate) of tumour-specific immune response-inducing peptides (cognate antigen) from the major histocompatibility class I (MHC-I) receptors of dendritic cells (DCs) originally at the vaccination site. For peptides with MHC-I off-rates beyond this transition, it is predicted that no vaccination strategy will lead to successful expansion of CTLs. For slower off-rates, below the transition, the probability of CTL activation becomes sensitive to the numbers of DCs and T cells that interact subsequent to DC migration to the draining lymph node of the vaccination site. Thus, the off-rate is a key determinant of vaccine design.


One-year Review of COVID-19 in the Arab World.
The coronavirus disease 2019 (COVID-19) has affected almost every country worldwide, including all 22 Arab countries. To the best of our knowledge, this is the first study to follow the prevalence of COVID-19 in all Arab countries. In this review, we aimed to assess the 12-month prevalence of COVID-19 in Arab countries and to compare these findings with other significantly affected countries. World Health Organization, Worldometer, and Ministries of Health websites were used to search for COVID-19 data in all Arab countries. The period covered started from February 2020 to February 2021. In all Arab countries, the median age of the population was 26.25 years. As of March 01, 2021, the total number of confirmed COVID-19 cases in all Arab countries was 4,259,756. Bahrain, Qatar, Lebanon, Kuwait, and United Arab Emirates had the highest reported number of confirmed COVID-19 cases per million population. The total number of COVID-19 deaths was 72,950, with predominance in Lebanon, followed by Tunisia, Jordan, Palestine, and Iraq. In comparison with the topmost affected countries, and based on both the highest number of confirmed and deaths per million population, Arab countries ranked second last before India, with 9,646 and 165 cases, respectively. Among the Arab countries, Qatar, Bahrain, and Lebanon showed the highest number of recovered, confirmed, and death cases per million populations, respectively. The number of confirmed and death cases among all Arab countries triggered significant worries about morbidity and mortality of COVID-19, respectively. However, the younger population in Arab countries may have contributed to fewer COVID-19 deaths in comparison with the topmost affected countries.


The mode of sensitization and its influence on allograft outcomes in highly sensitized kidney transplant recipients.
We sought to determine whether the mode of sensitization in highly sensitized patients contributed to kidney allograft survival. An analysis of the United Network for Organ Sharing dataset involving all kidney transplants between 1997 and 2014 was undertaken. Highly sensitized adult kidney transplant recipients [panel reactive antibody (PRA) ≥98%] were compared with adult, primary non-sensitized and re-transplant recipients. Kaplan-Meier survival analyses were used to determine allograft survival rates. Cox proportional hazards regression analyses were conducted to determine the association of graft loss with key predictors. Fifty-three percent of highly sensitized patients transplanted were re-transplants. Pregnancy and transfusion were the only sensitizing event in 20 and 5%, respectively. The 10-year actuarial graft survival for highly sensitized recipients was 43.9% compared with 52.4% for non-sensitized patients, P < 0.001. The combination of being highly sensitized by either pregnancy or blood transfusion increased the risk of graft loss by 23% [hazard ratio (HR) 1.230, confidence interval (CI) 1.150-1.315, P < 0.001], and the combination of being highly sensitized from a prior transplant increased the risk of graft loss by 58.1% (HR 1.581, CI 1.473-1.698, P < 0.001). The mode of sensitization predicts graft survival in highly sensitized kidney transplant recipients (PRA ≥98%). Patients who are highly sensitized from re-transplants have inferior graft survival compared with patients who are highly sensitized from other modes of sensitization.


Paranoid Thoughts in Adolescents with Social Anxiety Disorder.
Recently, social anxiety disorder (SAD) and paranoia have been demonstrated to be closely related. However, data were primarily drawn from adult community samples or patients with schizophrenia. The present study used a cross-sectional design to evaluate a sample of adolescents with SAD (n = 30, mean age 15.3 ± 0.9 years) compared with an age- and sex-matched group of healthy controls (n = 26, mean age 15.9 ± 1.6 years). The SAD group displayed more frequent and intense paranoid thoughts than the control group (t = 4.16, p < 0.001). The level of paranoid thoughts was significantly predicted by the degree of social phobia, even after adjusting for sex and other anxiety disorders, although adjusting for depression slightly reduced the extent and significance of the prediction. A lack of awareness about the association between SAD and paranoia may lead to incorrect diagnoses (e.g. misdiagnosis of psychotic disorders), or it may negatively influence the (psycho)therapeutic process and patient outcomes.


Socio-economic condition and lack of virological suppression among adults and adolescents receiving antiretroviral therapy in Ethiopia.
The potential impact of socio-economic condition on virological suppression during antiretroviral treatment (ART) in sub-Saharan Africa is largely unknown. In this case-control study, we compared socio-economic factors among Ethiopian ART recipients with lack of virological suppression to those with undetectable viral load (VL). Cases (VL>1000 copies/ml) and controls (VL<150 copies/ml) aged ≥15years, with ART for >6 months and with available VL results within the last 3 months, were identified from registries at public ART clinics in Central Ethiopia. Questionnaire-based interviews on socio-economic characteristics, health condition and transmission risk behavior were conducted. Univariate variables associated with VL>1000 copies/ml (p<0.25) were added to a multivariable logistic regression model. Among 307 participants (155 cases, 152 controls), 61.2% were female, and the median age was 38 years (IQR 32-46). Median HIV-RNA load among cases was 6,904 copies/ml (IQR 2,843-26,789). Compared to controls, cases were younger (median 36 vs. 39 years; p = 0.004), more likely to be male (46.5% vs. 30.9%; p = 0.005) and had lower pre-ART CD4 cell counts (170 vs. 220 cells/μl; p = 0.009). In multivariable analysis of urban residents (94.8%), VL>1000 copies/ml was associated with lower relative wealth (adjusted odds ratio [aOR] 2.98; 95% CI 1.49-5.94; p = 0.016), geographic work mobility (aOR 6.27, 95% CI 1.82-21.6; p = 0.016), younger age (aOR 0.94 [year], 95% CI 0.91-0.98; p = 0.011), longer duration of ART (aOR 1.19 [year], 95% CI 1.07-1.33; p = 0.020), and suboptimal (aOR 3.83, 95% CI 1.33-10.2; p = 0.048) or poor self-perceived wellbeing (aOR 9.75, 95% CI 2.85-33.4; p = 0.012), after correction for multiple comparisons. High-risk sexual behavior and substance use was not associated with lack of virological suppression. Geographic work mobility and lower relative wealth were associated with lack of virological suppression among Ethiopian ART recipients in this predominantly urban population. These characteristics indicate increased risk of treatment failure and the need for targeted interventions for persons with these risk factors.


Enhanced performance of supported HfO2 counter electrodes for redox couples used in dye-sensitized solar cells.
Mesoporous-graphitic-carbon-supported HfO2 (HfO2 -MGC) nanohybrids were synthesized by using a soft-template route. Characterization and a systematic investigation of the catalytic properties, stability, and catalytic mechanism were performed for HfO2 -MGC counter electrodes (CEs) in dye-sensitized solar cells (DSSCs). The new HfO2 -MGC as a CE in DSSCs showed a surprisingly high efficiency of 7.75 % for the triiodide/iodide redox couple and 3.69 % for the disulfide/thiolate redox couple, greater than the Pt electrode in the corresponding electrolyte system, which opens up a possibility for its practical application.


Prevalence of airflow obstruction and reduced forced vital capacity in an Aboriginal Australian population: The cross-sectional BOLD study.
Mortality and hospital separation data suggest a higher burden of chronic obstructive pulmonary disease (COPD) in indigenous than non-indigenous subpopulations of high-income countries. This study sought to accurately measure the true prevalence of post-bronchodilator airflow obstruction and forced vital capacity reduction in representative samples of Indigenous and non-Indigenous Australians. This study applies cross-sectional population-based survey of Aboriginal and non-Indigenous residents of the Kimberley region of Western Australia aged 40 years or older, following the international Burden Of Lung Disease (BOLD) protocol. Quality-controlled spirometry was conducted before and after bronchodilator. COPD was defined as Global initiative for chronic Obstructive Lung Disease (GOLD) Stage 2 and above (post-bronchodilator forced expiratory volume in 1 s/forced vital capacity (FEV1 /FVC) ratio <0.7 and FEV1 < 80% predicted). Complete data were available for 704 participants. The prevalence of COPD, adjusted for age, gender and body weight in Aboriginal participants (7.2%, 95% confidence interval (CI) 3.9 to 10.4) was similar to that seen in non-Indigenous Kimberley participants (8.2%, 95% CI 5.7 to 10.7) and non-Indigenous residents of the remainder of Australia (7.1%, 95% CI 6.1 to 8.0). The prevalence of low FVC (<80% predicted) was substantially higher in Aboriginal compared with non-Indigenous participants (74.0%, 95% CI 69.1 to 78.8, vs 9.7%, 95% CI 7.1 to 12.4). Low FVC, rather than airflow obstruction, characterizes the impact of chronic lung disease previously attributed to COPD in this population subject to significant social and economic disadvantage. Environmental risk factors other than smoking as well as developmental factors must be considered. These findings require further investigation and have implications for future prevention of chronic lung disease in similar populations.


Cognitive components of social capital and mental health status among older adults: a population-based cross-sectional study.
To determine the associations between the cognitive aspects of social capital and mental health status in older adults. Data on older people (65 years of age or older, n = 1,102) were retrieved from a general population mental health survey conducted in Finland in 2008. The response rate was 61%. The associations between self-reported depression (measured by the Composite International Diagnostic Interview Short Form, CIDI-SF) or psychological distress (measured by the General Health Questionnaire, GHQ-12) and perceived social support, sense of belonging, and trust were tested by logistic regression analyses. For the cognitive social capital indicators, difficult access to help from neighbours showed a significant association with depression. Furthermore, not having people to count on, experiencing a lack of concern from other people, and feeling mistrust towards other people were all significantly associated with psychological distress. Links between mental health and cognitive social capital indicate that social support and trust may be important factors to consider when developing interventions to promote mental health and prevent mental disorders among older adults.


Subtelomeric proteins negatively regulate telomere elongation in budding yeast.
The Tbf1 and Reb1 proteins are present in yeast subtelomeric regions. We establish in this work that they inhibit telomerase-dependent lengthening of telomere. For example, tethering the N-terminal domain of Tbf1 and Reb1 in a subtelomeric region shortens that telomere proportionally to the number of domains bound. We further identified a 90 amino-acid long sequence within the N-terminal domain of Tbf1 that is necessary but not sufficient for its length regulation properties. The role of the subtelomeric factors in telomere length regulation is antagonized by TEL1 and does not correlate with a global telomere derepression. We show that the absence of TEL1 induces an alteration in the structure of telomeric chromatin, as defined biochemically by an increased susceptibility to nucleases and a greater heterogeneity of products. We propose that the absence of TEL1 modifies the organization of the telomeres, which allows Tbf1 and Reb1 to cis-inhibit telomerase. The involvement of subtelomeric factors in telomere length regulation provides a possible mechanism for the chromosome-specific length setting observed at yeast and human telomeres.


Variants of ubiquitin-specific peptidase 24 play a crucial role in lung cancer malignancy.
Ubiquitin is a critical modifier regulating the degradation and function of its target proteins during posttranslational modification. Here we found that ubiquitin-specific peptidase 24 (USP24) is highly expressed in cell lines with enhanced malignancy and in late-stage lung cancer clinical samples. Studying single-nucleotide polymorphisms (SNPs) of USP24 using genomic DNA of lung cancer patients revealed an increase in SNP 7656C/T. When using RNA specimens instead of the genomic DNA of lung cancer patients, we found significant increases in the ratios of variants 930C/T and 7656T/C, suggesting that variants at these two sites are not only caused by the SNP of DNA but also by the RNA editing. USP24-930T and USP24-7656C increase USP24 expression levels by increasing RNA stability. Knocking down USP24 increased Suv39h1 level through a decrease in mouse double-minute 2 homolog levels, thus enhancing lysine-9 methylation of histone H3, and resulting in the prevention of lung cancer malignancy. In conclusion, as USP24 variant analysis revealed a higher ratio of variants in blood specimens of lung cancer patients than that in normal individuals, USP24-930T and USP24-7656C might be useful as diagnostic markers for cancer detection.


Representing actions through their sound.
Since the discovery of 'mirror neurons' in the monkey premotor and parietal cortex, an increasing body of evidence in animals and humans alike has supported the notion of the inextricable link between action execution and action perception. Although research originally focused on the relationship between performed and viewed actions, more recent studies highlight the importance of representing the actions of others through audition. In the first part of this article, we discuss animal studies, which provide direct evidence that action is inherently linked to multi-sensory cues, as well as the studies carried out on healthy subjects by using state-of-the-art cognitive neuroscience techniques such as functional magnetic resonance imaging (fMRI), event-related potentials (ERP), magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS). In the second section, we review the lesion analysis studies in brain-damaged patients demonstrating the link between 'resonant' fronto-parieto-temporal networks and the ability to represent an action by hearing its sound. Moreover, we examine the evidence in favour of somatotopy as a possible representational rule underlying the auditory mapping of actions and consider the links between language and audio-motor action mapping. We conclude with a discussion of some outstanding questions for future research on the link between actions and the sounds they produce.


Rates of hospitalization among African American and Caucasian American patients with Crohn's disease seen at a tertiary care center.
There is equivocal evidence regarding differences in the clinical course and outcomes of Crohn's disease (CD) among African Americans compared with Caucasian Americans. We sought to analyze whether African Americans with CD are more likely to be hospitalized for CD-related complications when compared with Caucasian Americans with CD. We conducted a retrospective cohort study including 909 African Americans and Caucasian Americans with CD who were seen at our tertiary care Inflammatory Bowel Disease (IBD) referral center between 2000 and 2013. We calculated the rate of hospitalization for CD-related complications among African Americans and Caucasian Americans separately. Zero-inflated Poisson regression models with robust variance estimates were used to estimate crude and multivariable adjusted rate ratios (RR) for CD-related hospitalizations. Multivariable adjusted models included adjustment for age, sex, duration of CD, smoking and CD therapy. The cumulative rate of CD-related hospital admissions was higher among African American patients compared with Caucasian American patients (395.6/1000 person-years in African Americans vs. 230.4/1000 person-years in Caucasian Americans). Unadjusted and multivariable adjusted rate ratios for CD-related hospitalization comparing African Americans and Caucasian Americans were 1.59 (95% confidence interval [95%CI]: 1.10-2.29; P=0.01) and 1.44 (95%CI: 1.02-2.03; P=0.04), respectively. African Americans with CD followed at a tertiary IBD-referral center had a higher rate for CD-related hospitalizations compared with Caucasian Americans. Future studies should examine whether socioeconomic status and biologic markers of disease status could explain the higher risk observed among African Americans.


Surprising trunk rotational capabilities in chimpanzees and implications for bipedal walking proficiency in early hominins.
Human walking entails coordinated out-of-phase axial rotations of the thorax and pelvis. A long-held assumption is that this ability relies on adaptations for trunk flexibility present in humans, but not in chimpanzees, other great apes, or australopithecines. Here we use three-dimensional kinematic analyses to show that, contrary to current thinking, chimpanzees walking bipedally rotate their lumbar and thoracic regions in a manner similar to humans. This occurs despite differences in the magnitude of trunk motion, and despite morphological differences in truncal 'rigidity' between species. These results suggest that, like humans and chimpanzees, early hominins walked with upper body rotations that countered pelvic rotation. We demonstrate that even if early hominins walked with pelvic rotations 50% larger than humans, they may have accrued the energetic and mechanical benefits of out-of-phase thoracic rotations. This would have allowed early hominins to reduce work and locomotor cost, improving walking efficiency early in hominin evolution.


Circulating levels of p,p'-DDE are related to prevalent hypertension in the elderly.
Polychlorinated biphenyls (PCBs) and dioxin given to experimental animals increase the blood pressure. We therefore investigated if circulating levels of persistent organic pollutants (POPs) were related to hypertension in a population-based sample of men and women. One thousand and sixteen subjects aged 70 years were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Twenty-three POPs were analyzed using high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS). Hypertension was defined as a systolic blood pressure ≥140mmHg or a diastolic blood pressure ≥90mmHg, and/or use of antihypertensive medication. Seven hundred and thirty-two subjects (72%) showed hypertension. When the POPs were treated as continuous variables and adjusted for gender only, two PCBs with a low number of chlorine atoms (PCB 105 and 118) were related to prevalent hypertension. Also the OC pesticide p,p'-DDE was related to hypertension. The strongest of these associations was seen for p,p'-DDE (OR 1.35 for a 1 SD change, 95% CI 1.17-1.56, p<0.0001). Following further adjustment also for BMI, smoking status, education level and exercise habits, only p,p'-DDE was still significantly related to hypertension (OR 1.23 for a 1 SD change, 95% CI 1.06-1.43, p=0.006). In this cross-sectional analysis of an elderly population, high levels of circulating levels of p,p'-DDE were associated with prevalent hypertension, further strengthening the experimental findings that POPs might influence blood pressure.


Home visiting and outcomes of preterm infants: a systematic review.
Home visiting is 1 strategy to improve child health and parenting. Since implementation of home visiting trials 2 decades ago, US preterm births (<37 weeks) have risen by 20%. The objective of this study was to review evidence regarding home visiting and outcomes of preterm infants Searches of Medline, Cumulative Index to Nursing and Allied Health Literature, Cochrane Database of Systematic Reviews, Cochrane Controlled Trial Register, PsycINFO, and Embase were conducted. Criteria for inclusion were (1) cohort or controlled trial designs; (2) home-based, preventive services for infants at medical or social risk; and (3) outcomes reported for infants born preterm or low birth weight (<2500 g). Data from eligible reports were abstracted by 2 reviewers. Random effects meta-analysis was used to synthesize data for developmental and parent interaction measures. Seventeen studies (15 controlled trials, 2 cohort studies) were reviewed. Five outcome domains were identified: infant development, parent-infant interaction, morbidity, abuse/neglect, and growth/nutrition. Six studies (n = 336) demonstrated a pooled standardized mean difference of 0.79 (95% confidence interval 0.57 to 1.02) in Home Observation for Measurement of the Environment Inventory scores at 1 year in the home-visited groups versus control. Evidence for other outcomes was limited. Methodological limitations were common. Reviewed studies suggest that home visiting for preterm infants promotes improved parent-infant interaction. Further study of interventions targeting preterm infants within existing programs may strengthen the impact and cost benefits of home visiting in at-risk populations.


The segmentation of colorectal MRI images.
One of the key criteria that informs patient management decisions for colorectal cancer is the extent of the shortest distance from the edge of the primary tumour to the edge of the mesorectum, also referred to as circumferential resection margin (CRM). This region is resected during surgery. The CRM is difficult for clinicians to measure accurately, particularly from 2D slice data. We present a method for automatically calculating and visualising the CRM distances in colorectal cancer MR images. We use local phase of the monogenic signal calculated from the MR image intensities to find edge and ridge features within the data. A non-parametric mixture model is then used to describe image intensity values within level set framework in order to segment the mesorectal fascia and the corresponding tumour and lymph nodes, as distinct regions. This segmentation is used to provide an automatic analysis of the shortest distance resection margin, and we show that this is consistent with that of the clinically accepted MERCURY method. We use the segmentation to provide a 3D visualisation of where the resection margin is smallest. Finally, we reconstruct a 3D map of the segmented anatomy. Both the visualisation methods provide a useful tool to aid surgeons in their treatment planning.


Genetic diversity and evolution of hepatitis C virus--15 years on.
In the 15 years since the discovery of hepatitis C virus (HCV), much has been learned about its role as a major causative agent of human liver disease and its ability to persist in the face of host-cell defences and the immune system. This review describes what is known about the diversity of HCV, the current classification of HCV genotypes within the family Flaviviridae and how this genetic diversity contributes to its pathogenesis. On one hand, diversification of HCV has been constrained by its intimate adaptation to its host. Despite the >30 % nucleotide sequence divergence between genotypes, HCV variants nevertheless remain remarkably similar in their transmission dynamics, persistence and disease development. Nowhere is this more evident than in the evolutionary conservation of numerous evasion methods to counteract the cell's innate antiviral defence pathways; this series of highly complex virus-host interactions may represent key components in establishing its 'ecological niche' in the human liver. On the other hand, the mutability and large population size of HCV enables it to respond very rapidly to new selection pressures, manifested by immune-driven changes in T- and B-cell epitopes that are encountered on transmission between individuals with different antigen-recognition repertoires. If human immunodeficiency virus type 1 is a precedent, future therapies that target virus protease or polymerase enzymes may also select very rapidly for antiviral-resistant mutants. These contrasting aspects of conservatism and adaptability provide a fascinating paradigm in which to explore the complex selection pressures that underlie the evolution of HCV and other persistent viruses.


Insights into the evolution of Archaea and eukaryotic protein modifier systems revealed by the genome of a novel archaeal group.
The domain Archaea has historically been divided into two phyla, the Crenarchaeota and Euryarchaeota. Although regarded as members of the Crenarchaeota based on small subunit rRNA phylogeny, environmental genomics and efforts for cultivation have recently revealed two novel phyla/divisions in the Archaea; the 'Thaumarchaeota' and 'Korarchaeota'. Here, we show the genome sequence of Candidatus 'Caldiarchaeum subterraneum' that represents an uncultivated crenarchaeotic group. A composite genome was reconstructed from a metagenomic library previously prepared from a microbial mat at a geothermal water stream of a sub-surface gold mine. The genome was found to be clearly distinct from those of the known phyla/divisions, Crenarchaeota (hyperthermophiles), Euryarchaeota, Thaumarchaeota and Korarchaeota. The unique traits suggest that this crenarchaeotic group can be considered as a novel archaeal phylum/division. Moreover, C. subterraneum harbors an ubiquitin-like protein modifier system consisting of Ub, E1, E2 and small Zn RING finger family protein with structural motifs specific to eukaryotic system proteins, a system clearly distinct from the prokaryote-type system recently identified in Haloferax and Mycobacterium. The presence of such a eukaryote-type system is unprecedented in prokaryotes, and indicates that a prototype of the eukaryotic protein modifier system is present in the Archaea.


Enantiomorphic normalization of focally lesioned brains.
In order to make spatial inferences about the brain across a group of patients, it is usually necessary to employ some means of bringing each brain image into register with either a group mean image or a standard template. In the presence of focal brain lesions, automated methods for performing such so-called normalization are liable to distortion from the abnormal signal within the lesion, especially when the non-linear warping necessary for maximum registration fidelity is used. The most frequently used method for minimizing this distortion--cost function masking--simply eliminates the lesioned area when deriving the normalization parameters. As lesion size increases, however, the normalization error may be expected to rise steeply since the volume of brain from which the parameters are derived falls with it. Here we propose an alternative non-linear registration method that exploits a natural redundancy in the brain--the enantiomorphic relation between the two hemispheres--to correct the signal within the lesion using information from the undamaged homologous region within the contralesional hemisphere. As lesion size increases, the normalization error should theoretically asymptote to inter-hemispheric differences, which are both quantifiable and much lower than the inter-subject difference. Using SPM's non-linear normalization routines, we evaluate this technique with images of normal brains to which lesions selected from a large dataset have been artificially applied. Our results show the enantiomorphic method to be vastly superior to cost function masking across subjects, lesion characteristics, and brain voxels. We therefore propose that it should be the method of choice for normalizing images of focally lesioned brains.


Intracellular pH measurements in gastric mucosa.
Intracellular pH was measured in bullfrog gastric mucosa using a pH-indicator dye, bromthymol blue (BTB), with a spectrophotometric technique. Studies showed that BTB is taken up by the gastric mucosa and bound to intracellular components. The binding of BTB was shown to cause a shift in the pKa of the dye from the solution value of 6.95 to a value of 8.0. During the nonsecreting state, intracellular pH was estimated to be 7.4 (metiamide inhibition) or 7.1 (SCN inhibition). During active secretion of acid, intracellular pH increased with increasing secretion rates, reaching values in excess of pH 8. Using preparations from which the surface epithelial cells had been removed, it was shown that at least a portion of the alkaline response to stimulation occurs in the oxyntic or tubular cells. The results are interpreted in view of existing models for the chemical reaction involved in gastric acid secretion.


First Report of Southern bean mosaic virus Infecting French Bean in Morocco.
Common bean (Phaseolus vulgaris L.) is grown on approximately 1,500 ha in commercial greenhouses and is of major economic importance in the Souss-Massa Region, Agadir, Morocco. Since October 2003, symptoms resembling a viral disease, consisting of pod mosaic and distortion and mild to severe mosaic in leaves, have been observed on bean plants in several greenhouses. Mechanical inoculation with symptomatic leaf extracts produced necrotic local lesions on P. vulgaris 'Pinto' and systemic symptoms similar to those observed in the naturally infected bean plants P. vulgaris 'Donna' (five plants per cultivar). Inoculated and naturally infected samples reacted positively using a double antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA) to Southern bean mosaic virus (SBMV) (DSMZ, Braunschweig, Germany), a member of the Sobemovirus genus that is transmitted by contact, soil, beetles, and seeds (1). Virions purified from a naturally infected 'Donna' plant contained a 30-kDa polypeptide that reacted positively using sodium dodecyl sulfate polyacrylamide gel electrophoresis and western blot analysis with SBMV antiserum (DSMZ). Reverse transcription-polymerase chain reaction amplification with SMBV primers as described by Verhoeven et al. (2) produced an expected 870-bp band. The amplicon was cloned, sequenced (GenBank Accession No. AJ748276), and compared to those isolates available in GenBank and had a nucleotide sequence identity of 87% and a derived amino acid sequence identity of 95% with an SBMV isolate from Spain (2). During a survey in different areas of the Souss-Massa Region, 20 symptomatic leaf and pod samples were randomly collected from 12 greenhouses (50 ha) where significant commercial losses were suffered because of this virus disease, and all samples were positive using DAS-ELISA for SBMV. To our knowledge, this is the first report of SBMV in Morocco. References: (1) J. H. Tremaine and R. I. Hamilton. Southern bean mosaic virus. No. 274 in: Descriptions of Plant Viruses. CMI/AAB, Kew, Surrey, England, 1983. (2) J. Th. J. Verhoeven et al. Eur. J. Plant Pathol. 109:935, 2003.


Association Between Polygenic Risk Score and Risk of Myopia.
Myopia is a leading cause of untreatable visual impairment and is increasing in prevalence worldwide. Interventions for slowing childhood myopia progression have shown success in randomized clinical trials; hence, there is a need to identify which children would benefit most from treatment intervention. To examine whether genetic information alone can identify children at risk of myopia development and whether including a child's genetic predisposition to educational attainment is associated with improved genetic prediction of the risk of myopia. Meta-analysis of 3 genome-wide association studies (GWAS) including a total of 711 984 individuals. These were a published GWAS for educational attainment and 2 GWAS for refractive error in the UK Biobank, which is a multisite cohort study that recruited participants between January 2006 and October 2010. A polygenic risk score was applied in a population-based validation sample examined between September 1998 and September 2000 (Avon Longitudinal Study of Parents and Children [ALSPAC] mothers). Data analysis was performed from February 2018 to May 2019. The primary outcome was the area under the receiver operating characteristic curve (AUROC) in analyses for predicting myopia, using noncycloplegic autorefraction measurements for myopia severity levels of less than or equal to -0.75 diopter (D) (any), less than or equal to -3.00 D (moderate), or less than or equal to -5.00 D (high). The predictor variable was a polygenic risk score (PRS) derived from genome-wide association study data for refractive error (n = 95 619), age of onset of spectacle wear (n = 287 448), and educational attainment (n = 328 917). A total of 383 067 adults aged 40 to 69 years from the UK Biobank were included in the new GWAS analyses. The PRS was evaluated in 1516 adults aged 24 to 51 years from the ALSPAC mothers cohort. The PRS had an AUROC of 0.67 (95% CI, 0.65-0.70) for myopia, 0.75 (95% CI, 0.70-0.79) for moderate myopia, and 0.73 (95% CI, 0.66-0.80) for high myopia. Inclusion in the PRS of information associated with genetic predisposition to educational attainment marginally improved the AUROC for myopia (AUROC, 0.674 vs 0.668; P = .02), but not those for moderate and high myopia. Individuals with a PRS in the top 10% were at 6.1-fold higher risk (95% CI, 3.4-10.9) of high myopia. A personalized medicine approach may be feasible for detecting very young children at risk of myopia. However, accuracy must improve further to merit uptake in clinical practice; currently, cycloplegic autorefraction remains a better indicator of myopia risk (AUROC, 0.87).


Morphologic features of carcinoid heart disease as assessed by three-dimensional transesophageal echocardiography.
Carcinoid heart disease (CHD) is a rare cause of valvular heart disease and carries a poor prognosis. CHD has a unique morphology and echocardiographic features that predominantly involve right-sided valvular structures. The diagnosis of CHD is usually made by two-dimensional transthoracic echocardiography (TTE). With the superior spatial resolution of real time three-dimensional transesophageal echocardiography (3DTEE), structural changes that occur in patients with CHD-associated valvular heart disease can be examined in greater detail. We undertook this study to examine the incremental value of 3DTEE in the diagnosis of CHD. A total of four patients with CHD underwent TTE, transesophageal echocardiography (TEE), and 3DTEE as part of their routine clinical evaluation. TTE and TEE for all four patients revealed thickened, fibrosed, retracted, and malcoapted tricuspid leaflets with wide-open tricuspid valve regurgitation. 3DTEE en face imaging of the tricuspid valve demonstrated the characteristic morphologic features of CHD more clearly in all four patients. 3DTEE provides substantial incremental value over TTE in the assessment of characteristic CHD pathology and thus enhances the echocardiographic diagnosis of CHD.


[Evaluation of the efficacy of a medicine bag printed with a photograph of the medicine for the prevention of drug-dispensing errors].
In this study, a survey was conducted to determine the rate of drug-dispensing errors with the use of medicine bags printed with photographs of prescribed medicines (hereafter "medicine bag") for a 6-week period from June 20 to July 31, 2005. During this period, 393928 prescriptions were filled in 127 medical facilities that use the medicine bag. The efficacy of the medicine bag in the prevention of drug-dispensing errors was investigated. A total of 6550 (1.66%) drug-dispensing errors were identified: 70.6% were identified at the inspecting stage; 27.4% at the providing medicine and information stage; and 2% after the medication was dispensed. The drug-dispensing errors identified in the inspecting and providing stages included a) using the wrong contents, b) dispensing the wrong drugs, c) missing drugs, d) calculation errors, e) weighing/measuring errors, and f) others. No significant difference was observed in the error rates; thus it was assumed that the type of error was not dependent on the stage at which dispensing errors was discovered. However, it was found that approximately 25% of errors at the providing stage were discovered as a result of the medicine bag. Errors of types a), b), and c) were often discovered because the photograph was printed on the medicine bag. Therefore it was assumed that the photographs contributed to the discovery of drug-dispensing errors.


Targeting of embryonic stem cells by peptide-conjugated quantum dots.
Targeting stem cells holds great potential for studying the embryonic stem cell and development of stem cell-based regenerative medicine. Previous studies demonstrated that nanoparticles can serve as a robust platform for gene delivery, non-invasive cell imaging, and manipulation of stem cell differentiation. However specific targeting of embryonic stem cells by peptide-linked nanoparticles has not been reported. Here, we developed a method for screening peptides that specifically recognize rhesus macaque embryonic stem cells by phage display and used the peptides to facilitate quantum dot targeting of embryonic stem cells. Through a phage display screen, we found phages that displayed an APWHLSSQYSRT peptide showed high affinity and specificity to undifferentiated primate embryonic stem cells in an enzyme-linked immunoabsorbent assay. These results were subsequently confirmed by immunofluorescence microscopy. Additionally, this binding could be completed by the chemically synthesized APWHLSSQYSRT peptide, indicating that the binding capability was specific and conferred by the peptide sequence. Through the ligation of the peptide to CdSe-ZnS core-shell nanocrystals, we were able to, for the first time, target embryonic stem cells through peptide-conjugated quantum dots. These data demonstrate that our established method of screening for embryonic stem cell specific binding peptides by phage display is feasible. Moreover, the peptide-conjugated quantum dots may be applicable for embryonic stem cell study and utilization.


High levels of diversity uncovered in a widespread nominal taxon: continental phylogeography of the neotropical tree frog Dendropsophus minutus.
Species distributed across vast continental areas and across major biomes provide unique model systems for studies of biotic diversification, yet also constitute daunting financial, logistic and political challenges for data collection across such regions. The tree frog Dendropsophus minutus (Anura: Hylidae) is a nominal species, continentally distributed in South America, that may represent a complex of multiple species, each with a more limited distribution. To understand the spatial pattern of molecular diversity throughout the range of this species complex, we obtained DNA sequence data from two mitochondrial genes, cytochrome oxidase I (COI) and the 16S rhibosomal gene (16S) for 407 samples of D. minutus and closely related species distributed across eleven countries, effectively comprising the entire range of the group. We performed phylogenetic and spatially explicit phylogeographic analyses to assess the genetic structure of lineages and infer ancestral areas. We found 43 statistically supported, deep mitochondrial lineages, several of which may represent currently unrecognized distinct species. One major clade, containing 25 divergent lineages, includes samples from the type locality of D. minutus. We defined that clade as the D. minutus complex. The remaining lineages together with the D. minutus complex constitute the D. minutus species group. Historical analyses support an Amazonian origin for the D. minutus species group with a subsequent dispersal to eastern Brazil where the D. minutus complex originated. According to our dataset, a total of eight mtDNA lineages have ranges >100,000 km2. One of them occupies an area of almost one million km2 encompassing multiple biomes. Our results, at a spatial scale and resolution unprecedented for a Neotropical vertebrate, confirm that widespread amphibian species occur in lowland South America, yet at the same time a large proportion of cryptic diversity still remains to be discovered.


First Report of Crown and Stem Rot of Crested Molded Wax Agave (Echeveria agavoides) caused by Fusarium oxysporum in Italy.
During March 2012, 95% of 24-month-old plants of crested molded wax agave (Echeveria agavoides), a succulent plant belonging to the Crassulaceae family, showed symptoms of a basal stem and leaf rot in a commercial farm near Ventimiglia (northern Italy). Affected plants showed extensive chlorosis from the crown level to the stem apex, followed by yellowing and by the appearance of a water-soaked aspect of stem and leaf tissues. As disease progressed, leaves became brown, wilted, and rotted. Wilting was at first unilateral and later affected the entire plant. Brown discoloration was observed in the vascular system of cut stems and leaves. In some cases, leaves were covered by a whitish-orange mycelium. This produced 3-septate, slightly curved macroconidia with a foot-shaped basal cell and a short apical cell, measuring 27.4 to 39.6 × 3.0 to 4.1 (average 34.2 × 3.7) μm and unicellular, ovoid to elliptical microconidia measuring 4.8 to 11.6 × 1.5 to 3.7 (avg. 7.2 × 2.7) μm. A fungus was consistently isolated from discolored vascular leaf tissues on Komada selective medium. Cultures on potato dextrose agar (PDA) and carnation leaf-piece agar (CLA) were incubated at 24 to 29°C. On PDA, a thin growth of whitish mycelium without pigments in the agar was observed. On CLA, sparse macroconidia, 18.9 to 30.7 × 3.0 to 4.2 (avg. 23.9 × 3.6) μm, microconidia, 4.7 to 7.7 × 1.7 to 3.1 (avg. 6.0 × 2.4) μm, and abundant chlamydospores that were single or paired, terminal and intercalary, rough walled, and 6.8 to 9.5 (avg. 7.7) in diameter were produced. Such characteristics are typical of Fusarium oxysporum (2). Amplification of the internal transcribed spacer (ITS) of the rDNA using primers ITS1/ITS4 (3) yielded a 486-bp band (GenBank Accession No. JX441893). Sequencing and BLASTn analysis of this band showed 100% identity and an E-value of 0.0 with the ITS sequence of F. oxysporum (JN232163). To confirm pathogenicity, five 3-month-old healthy plants of E. agavoides were inoculated by dipping unwounded roots in a conidial suspension (1.0 × 107 CFU/ml) of one isolate of F. oxysporum obtained from affected plants, grown for 10 days in potato dextrose broth. Plants were transplanted into pots filled with steam-sterilized substrate (sphagnum peat-perlite-pine bark-clay 50:20:20:10) and maintained in a glasshouse at 28 to 33°C. Five non-inoculated plants served as a control. Chlorosis and yellowing developed on the inoculated plants 15 days after the inoculation. Basal stem rot and vascular discoloration in the crown and stem developed within 30 days on inoculated plants. A whitish-orange mycelium producing macroconidia covered the affected leaves. Non-inoculated plants remained healthy. F. oxysporum was consistently reisolated from symptomatic plants. The pathogenicity test was conducted twice. A Fusarium sp. has been reported as the causal agent of a stem rot on Echeveria sp. in the U.S. (1). To our knowledge, this is the first report of F. oxysporum on E. agavoides in Italy. The disease is currently present in few nurseries, although it could spread, causing significant economic losses due to the increasing cultivation of E. agavoides in Italy. References: (1) D. F. Farr et al. Fungi on Plants and Plant Products in the United States. APS Press, St. Paul, MN, 1989. (2) J. F. Leslie and B. A. Summerell. The Fusarium Laboratory Manual. Blackwell, Ames, IA, 2006. (3) T. J. White et al. PCR Protocols: A Guide to Methods and Applications. M. A. Innis et al., eds. Academic Press, San Diego, 1990.


Fluorophotometric Analysis of the Ocular Surface Glycocalyx in Soft Contact Lens Wearers.
Unstable tear film characterized by shorting of tear break-up time (BUT) is associated with discomfort and dryness in contact lens wearers. The glycocalyx is thought to be crucial in maintaining the wettability and lubrication of the ocular surface. We evaluated the ocular surface glycocalyx in soft contact lens (SCL) wearers using a fluorescein-labeled wheat germ agglutinin (F-WGA) as a marker to demonstrate the ocular surface glycoconjugates in vivo. Twenty experienced SCL wearers and 20 healthy volunteers with no history of CL wearing (controls) were enrolled in the study. After applying a 5% F-WGA solution to the eyes of study individuals, fluorescent intensities in their respective central corneas were measured by fluorophotometry. The relationship between F-WGA intensity in the corneal surface and clinical parameters associated with contact lens wear were analyzed. F-WGA fluorescence intensity in the SCL group was 418.5 ± 103.3, which was significantly lower than that of the controls (825.0 ± 179.8; p < 0.0001, Mann-Whitney test). F-WGA fluorescence intensity was not correlated with Schirmer's test values or age, whereas a statistically significant correlation between F-WGA fluorescence intensity and tear film BUT was observed (r = 0.77, p < 0.0001). The decrease in F-WGA fluorescence intensity could be reversed by discontinuation of SCL use. Reduction and/or compositional alteration of ocular surface glycocalyx may be one of the causative factors of SCL-induced eye dryness.


The relationship between religious involvement and clinical status of patients with bipolar disorder.
Religion and spirituality are important coping strategies in depression but have been rarely studied within the context of bipolar disorder. The present study assessed the association between different forms of religious involvement and the clinical status of individuals treated for bipolar disorder. A cross-sectional observation study of follow-up data from a large cohort study of patients receiving care for bipolar disorder (n = 334) at an urban Veterans Affairs mental health clinic was conducted. Bivariate and multivariate analyses were performed to assess the association between public (frequency of church attendance), private (frequency of prayer/meditation), as well as subjective forms (influence of beliefs on life) of religious involvement and mixed, manic, depressed, and euthymic states when demographic, anxiety, alcohol abuse, and health indicators were controlled. Multivariate analyses found significant associations between higher rates of prayer/meditation and participants in a mixed state [odds ratio (OR) = 1.29; 95% confidence interval (CI) = 1.10-1.52, chi square = 9.42, df = 14, p < 0.05], as well as lower rates of prayer/meditation and participants who were euthymic (OR = 0.84; 95% CI = 0.72-0.99, chi square = 4.60, df = 14, p < 0.05). Depression and mania were not associated with religious involvement. Compared to patients with bipolar disorder in depressed, manic, or euthymic states, patients in mixed states have more active private religious lives. Providers should assess the religious activities of individuals with bipolar disorder in mixed states and how they may complement/deter ongoing treatment. Future longitudinal studies linking bipolar states, religious activities, and treatment-seeking behaviors are needed.


Patient Survey of Referral From One Surgeon to Another to Reduce Maximum Waiting Time for Elective Surgery and Hours of Overutilized Operating Room Time.
Studies of shared (patient-provider) decision making for elective surgical care have examined both the decision whether to have surgery and patients' understanding of treatment options. We consider shared decision making applied to case scheduling, since implementation would reduce labor costs. Study questions were presented in sequence of waiting times, starting with 4 workdays. "Assume the consultant surgeon (ie, the surgeon in charge) you met in clinic did not have time available to do your surgery within the next 4 workdays, but his/her colleague would have had time to do your surgery within the next 4 workdays. Would you have wanted to discuss with a member of the surgical team (eg, the scheduler or the surgeon) the availability of surgery with a different, equally qualified surgeon at Mayo Clinic who had time available within the next 4 workdays, on a date of your choosing?" There were 980 invited patients who underwent lung resection or cholecystectomy between 2011 and 2016; 135 respondents completed the study and 6 respondents dropped out after the study questions were displayed. The percentages of patients whose response to the study questions was "4 days" were 58.8% (40/68) among lung resection patients and 58.2% (39/67) among cholecystectomy patients. The 97.5% 2-sided confidence interval for the median maximum wait was 4 days to 4 days. Patients' choices for the waiting time sufficient to discuss having another surgeon perform the procedure did not differ between procedures (P = .91). Results were insensitive to patients' sex, age, travel time to hospital, or number of office visits before surgery (all P ≥ .20). Our results indicate that bringing up the option with the patient of changing surgeons when a colleague is available and has the operating room time to perform the procedure sooner is being respectful of most patients' individual preferences (ie, patient-centered).


Cysteinyl Leukotrienes as Potential Pharmacological Targets for Cerebral Diseases.
Cysteinyl leukotrienes (CysLTs) are potent lipid mediators widely known for their actions in asthma and in allergic rhinitis. Accumulating data highlights their involvement in a broader range of inflammation-associated diseases such as cancer, atopic dermatitis, rheumatoid arthritis, and cardiovascular diseases. The reported elevated levels of CysLTs in acute and chronic brain lesions, the association between the genetic polymorphisms in the LTs biosynthesis pathways and the risk of cerebral pathological events, and the evidence from animal models link also CysLTs and brain diseases. This review will give an overview of how far research has gone into the evaluation of the role of CysLTs in the most prevalent neurodegenerative disorders (ischemia, Alzheimer's and Parkinson's diseases, multiple sclerosis/experimental autoimmune encephalomyelitis, and epilepsy) in order to understand the underlying mechanism by which they might be central in the disease progression.


Jointly Embedding Multiple Single-Cell Omics Measurements.
Many single-cell sequencing technologies are now available, but it is still difficult to apply multiple sequencing technologies to the same single cell. In this paper, we propose an unsupervised manifold alignment algorithm, MMD-MA, for integrating multiple measurements carried out on disjoint aliquots of a given population of cells. Effectively, MMD-MA performs an in silico co-assay by embedding cells measured in different ways into a learned latent space. In the MMD-MA algorithm, single-cell data points from multiple domains are aligned by optimizing an objective function with three components: (1) a maximum mean discrepancy (MMD) term to encourage the differently measured points to have similar distributions in the latent space, (2) a distortion term to preserve the structure of the data between the input space and the latent space, and (3) a penalty term to avoid collapse to a trivial solution. Notably, MMD-MA does not require any correspondence information across data modalities, either between the cells or between the features. Furthermore, MMD-MA's weak distributional requirements for the domains to be aligned allow the algorithm to integrate heterogeneous types of single cell measures, such as gene expression, DNA accessibility, chromatin organization, methylation, and imaging data. We demonstrate the utility of MMD-MA in simulation experiments and using a real data set involving single-cell gene expression and methylation data.


Cardiovascular risk profiles of world masters games participants.
Increasing evidence indicates adherence to exercise throughout life is concurrent with improved health. World masters games (WMG) have more participants than any other international sporting competition and is under investigated, particularly with regard to indices of cardiovascular disease risk. Therefore, we chose to investigate selected cardiovascular risk factors in WMG participants. This was a cross-sectional, observational study which utilized a web-based questionnaire to survey cardiovascular risk factors of WMG participants. The survey consisted of three sections: basic demographics, medical history and physiological parameters which included Body Mass Index (BMI), waist circumference (WC), resting blood pressure (BP) and lipids (total cholesterol [TC], high density lipoprotein [HDL] and low density lipoprotein [LDL]). A total of 1435 participants, 872 male, aged 27-91 years (mean age 54.99 years) participated in the study. Key findings included significant differences (P<0.05) between genders in BMI (17.7%, P<0.001), WC (10.6%, P<0.001), resting SBP (5.8%, P<0.001) and resting DBP (4.8%, P<0.001). Significant differences were also found between genders in HDLs (15.2%, P<0.001), TC:HDL ratio (17.2%, P<0.001) and LDL:HDL ratio (19.0%, P<0.001). Significant differences (P<0.001) were also identified when comparing WMG lipid results to the Australian general population (TC P<0.001; HDLs P<0.001; LDLs P<0.001). A high percentage of WMG participants demonstrated optimal values in a number of cardiovascular disease (CVD) risk factors when compared to the general population, female WMG participants had better values as compared to males. This reflected a decreased CVD in WMG participants and supports our hypothesis of enhanced health characteristics in an active, but aged cohort.